Abstract: The Kaposi's Sarcoma-associated Herpesvirus (KSHV) is the etiologic agent of several human cancers, including Kaposi's Sarcoma (KS) and Primary Effusion Lymphoma (PEL), which preferentially arise in immunocompromised patients and lack any effective therapeutic options. Human Endogenous Retrovirus Sequences (HERVs) constitute up to 8% of the human genome, yet not all HERVs remain silent passengers within our genomes. Some HERVs, especially the HERV type K (HERV-K), have been found to be frequently reactivated in patients with immunodeficiency, and in a variety of inflammatory diseases and human cancers. However, the role of HERV-K transactivation in viral oncogenesis, such as KSHV-related malignancies, remains unknown. Our preliminary data indicate that either KSHV de novo infection or ectopic expression of KSHV-encoded latent protein can transactivate the HERV-K from both host primary and tumor cells. We also found higher levels of HERV-K transactivation in the Peripheral Blood Mononuclear Cells (PBMCs) from HIV+/KSHV+ patients than those from HIV+/KSHV- patients. There is a strong expression of HERV-K-encoded oncoprotein, NP9, within KS tissues isolated from our cohort of untreated AIDS patients. Further data indicate that HERV-K transactivation or the induction of HERV-K-NP9 protein expression is responsible for cell invasiveness and anchorage-independent growth of KSHV-infected endothelial cells. Based on these data, we hypothesize that transactivation of HERV-K may act as an important co-factor for KSHV pathogenesis and the development of virus-related malignant transformation. Therefore, targeting the transactivation of HERV-K could serve as a new interventional strategy against these malignances. To address this hypothesis, we propose the following Specific Aims: 1) To identify mechanism/s through which KSHV-encoded latent protein, LANA, transactivates HERV-K in the host cells. 2) To determine the role of HERV-K transactivation (particularly HERV-K-encoded oncogenic NP9 protein) in the pathogenesis of KSHV-infected cells in vitro and in vivo. 3) To assess the therapeutic value of targeting HERV-K NP9 protein against KSHV- induced tumorigenesis in vivo. Through these efforts, we aim to understand the role of HERV-K in the development of KSHV-related malignancies. This could also help elucidate the role of HERV-K transactivation in the pathogenesis of other herpesviruses or the progression of other human cancers. Additionally, these studies will provide the framework for the development of interventional strategies targeting HERV-K transactivation and its associated mechanisms for the treatment and/or prevention of KSHV-related malignancies in high-risk immunocompromised patients. !